Creatinine‐to‐Cystatin C Ratio and Disability Trajectories: A Muscle Biomarker or a Composite Physiological Signal?

Dear Editor,

1.

We read with great interest the study by Wu et al., investigating the association between the serum creatinine‐to‐cystatin C ratio (CCR) and trajectories of activities of daily living (ADL), basic activities of daily living (BADL), and instrumental activities of daily living (IADL) disability among middle‐aged and older Chinese adults [1]. Based on approximately 10 years of repeated follow‐up, the authors identified three distinct disability trajectories and found that a higher baseline CCR was associated with a lower probability of being classified into the increasing‐disability trajectory group. These findings highlight the potential value of routinely available laboratory indicators for functional risk stratification. However, the clinical interpretation of CCR warrants further consideration, as it may represent a composite physiological signal rather than a direct measure of skeletal muscle status.

CCR is commonly regarded as a surrogate marker of muscle mass, based on the rationale that serum creatinine is partly determined by skeletal muscle creatine metabolism, whereas cystatin C is less dependent on muscle mass [2, 3]. Although this interpretation is biologically plausible, it may oversimplify the physiological information captured by CCR. In fact, neither component is specific to skeletal muscle. Serum creatinine is influenced by kidney function, dietary intake, age, sex, and muscle metabolism, whereas cystatin C, despite being less dependent on muscle mass, can also be affected by age, obesity, smoking, inflammation, and metabolic conditions independent of measured glomerular filtration rate [4, 5]. Therefore, a low CCR may reflect reduced muscle reserve, impaired kidney function, systemic illness, or a combination of these conditions. This distinction is particularly important when functional disability is the outcome, as kidney dysfunction, inflammation, and multimorbidity can independently contribute to functional decline.

The influence of kidney function on CCR interpretation also deserves further consideration. In the current study, chronic kidney disease was included as a covariate; however, its definition was partly based on creatinine‐derived estimated glomerular filtration rate [1]. Because creatinine serves both as a component of CCR and as an important marker of renal function assessment, adjustment using creatinine‐derived renal indices may not completely separate muscle‐related information from kidney‐related information contained within CCR. This potential coupling may complicate the interpretation of CCR as an independent indicator of muscle status. Particularly among older adults, renal impairment, inflammatory states, and multimorbidity may simultaneously influence creatinine and cystatin C levels and subsequently affect functional outcomes. Future studies incorporating kidney function–stratified analyses, renal assessment methods less dependent on creatinine, or sensitivity analyses across different levels of renal function may help determine whether CCR provides functional prognostic information independent of kidney status.

Wu et al. provide important evidence that CCR can identify individuals with different long‐term disability trajectories. We suggest that the clinical value of CCR may be better understood as a composite biomarker reflecting muscle‐related biological changes and overall systemic health rather than as a stand‐alone surrogate for sarcopenia. Further investigations incorporating more rigorous control of kidney function, direct measurements of muscle mass, and objective functional assessments will help clarify the biological information captured by CCR in predicting functional decline.

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Conflicts of Interest

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Data Availability Statement

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